Several families with rare genetic forms of Parkinson's disease have been identified, and at present mutations in three genes implicated in familial forms of parkinsonism have been described: the alpha-synuclein gene, the ubiquitin carboxy- terminal hydrolase-L1 gene (UCH-L1), and the parkin gene, in which most mutations are found, leading to an early onset form of parkinsonism. In addition several new localizations of genes have been reported for which the responsible genes have not yet been identified.
Although these familial forms of the disease are relatively rare compared to the total number of people with PD, the identification of their genetic defects has provided tremendous contributions toward our understanding of the mechanisms that take place during the course of the disease.
In particular, the findings that Lewy bodies contain a ubiquitinated form of alpha-synuclein and that UCH-L1 and parkin both are involved in a specific protein degradation pathway have implicated abnormal protein degradation mediated in both familial and sporadic forms of PD (similar to other neurodegenerative disorders such as Alzheimer's disease). Finding additional genes that increase the risk for developing PD may strengthen the evidence of the involvement of this pathway in the pathogenesis of PD.
Researchers also have suggested the involvement of other biochemical pathways such as protection against oxidative stress in PD. Recently, we identified a new locus involved in autosomal recessive early-onset parkinsonism, PARK7, to a chromosome 1p36. We subsequently started working toward identifying the responsible gene and identified pathogenic mutations in the DJ-1 gene.
The function of DJ-1 is largely unknown but there are indications that it is involved in the cellular response to oxidative damage. Therefore, the aim of this project is to characterize the function of DJ-1 in detail and study how mutations in this gene can lead to Parkinson's disease. This research will possibly provide us with a new opening to develop more efficient therapies for the treatment of Parkinson's disease.